This invention relates to a diafiltration method and apparatus for separating a whole blood into its cellular component and its plasma component and further separating the plasma component to isolate plasma components such as those components that cause disease.
Diafiltration comprises an ultrafiltration process wherein a liquid composition is separated utilizing a membrane into a stream containing solute retained by the membrane (retentate stream) and a second stream containing solutes which pass the membrane (permeate stream). In the diafiltration process, the retentate stream is recycled to the separation membrane after a diluent has been added. In constant volume batch diafiltration the rate of diluent addition is equal to the flow rate of the permeate stream and the retentate volume remains constant.
Membrane plasmapheresis can be employed to remove large molecular species of proteins in the plasma that cause disease such as immunologically based diseases or other disease states resulting from excessive concentrations of pathogenic plasma proteins. Presently available processes include a first step wherein blood removed from a patient is separated into its cellular component and its plasma component. The cellular component is recirculated to the patient while the plasma component is treated further to separate a large molecular fraction having a molecular weight above about 70,000 daltons which fraction contains the disease causing protein fraction. The relatively low molecular weight fraction contains proteins required by the patient such as albumin also is recirculated to the patient. The separation of the high nolecular weight plasma fraction from the low molecular weight plasma fraction is accomplished with an ultrafiltration membrane having a pore size that allows passage of the low molecular weight fraction while retaining the high molecular weight fraction.
During the extracorporeal treatment of the plasma, the passage of protein and albumin through the membrane is significantly reduced as the concentration of the rejected high molecular weight fraction increases. This occurs since the general mode of operation is to recirculate the high molecular weight fraction to a reservoir wherein it is admixed with incoming fresh plasma and a diluent such as saline. The resulting composition then is recirculated to the ultrafiltration membrane. The diluent is added to reduce the concentration of the high molecular weight fraction in the recirculation loop and thereby reduce plugging of the membrane pores. If too little diluent is employed undesired pore plugging results. If excessive diluent is employed a larger ultrafiltration membrane area is required and the stream recirculated in the patient will contain undesirably high concentrations of the diluent. Consequently, presently available ultrafiltration modules operate at low separation efficiencies and at high recirculation rates (high tangential shear rates). Also, presently available systems operate at fluxes sufficiently low to accommodate the concentration build up in the recirculation loop and therefore require a large excess of ultrafiltration membrane area.
Smeby et al in PCT international application number PCT/NO 83/00025 disclose a process for separating a plasma fraction into a high molecular weight fraction and a low molecular weight fraction. The process utilizes an extracorporeal cascade filtration device having a recycle loop which includes a variable volume reservoir and utilizes a large dilution in the recycle loop. The process is designed and operated to respond dynamically to the lowering flux associated with accumulated protein in this reservoir by lowering the permeate volumetric flow rate from the primary filter (which separate blood cellular components from blood plasma components) to match the maximum flow rate achievable from the secondary plasma filter (which separates the high molecular weight plasma fraction from the low molecular weight plasma fraction) which flow rate is reduced as flux decreases. An additional third filter which is completely retentive of all proteins is included in the apparatus to (a) concentrate the albumin recovered at low concentration (resulting from excess membrane area) and (b) return the water removed by the filter to the recirculation reservoir thereby to dilute the accumlated protein and thereby recover flux. The system is undesirable since it requires excessive membrane area and controls flux by reducing volumetric flow rates rather than by utilizing a mode of operation which permits maintaining higher flux.
U.S. Pat. No. 4,350,156 to Malchesky et al discloses a process for treating plasma to remove macromolecules having a molecular weight greater than about 70,000 daltons in order to provide therapeutic treatment of various disease states. Whole blood is first separated into its cellular components and its plasma component. The plasma component is cooled, filtered to retain the macromolecules while permitting passage of the smaller molecular component such as albumin through the filter. The cellular components and the plasma components passed through the filter then are recycled to the patient. Prior to being filtered, the plasma is cooled to a temperature of about 10.degree. C. The primary problem with this mode of operation is that the membrane filter quickly becomes clogged which results in a low percentage of albumin being passed through the filter for recycling to the patient. This requires that make up albumin be supplied to the patient during the plasmapheresis treatment.
U.S. Pat. No. 4,350,594 to Kawei et al discloses a two step blood treatment process wherein whole blood is separated into its plasma component and its cellular component in a first step. In the second step, the plasma component is separated into a high molecular weight fraction and a low molecular weight fraction. The low molecular weight fraction and the cellular component are recirculated to the patient. This patent discloses that substitute fluids such as saline, anticoagulant or the like are introduced into the system at a rate equal to the rate of removal of the high molecular weight plasma fraction. There is no disclosure of the use of a recirculation loop to recirculate the high molecular weight fraction to the second separation step in order to improve the efficiency of the plasma separation. As a result, large amounts of albumin are lost with the discarded high molecular weight fraction particularly after the apparatus has been in use and the membrane utilized to separate the plasma fraction gradually has become plugged. Accordingly, albumin must be supplied independently from a source other than the patient which increases the risk of the introduction of disease and possible adverse immunological reaction period. U.S. Pat. No. 4,191,182 to Popovich et al discloses a process for treatment whole blood wherein the cellular components are separated from the plasma utilizing an ultrafiltration membrane. A portion of the cellular components are recycled for admixture with incoming whole blood in order to improve the separation efficiency of the membrane. This patent does not disclose any particular means for further fractionating the plasma component.
U.S. Pat. Nos. 4,215,688 and 4,223,672 to Terman et al discloses a method and apparatus for treating whole blood which includes separating whole blood into its cellular component and its plasma component and subsequently treating the plasma component by contacting it with an immunoadsorbant in order to remove a particular antigen, antibody or antigen-antibody complex from the blood. Neither of these patents discloses separating the plasma component into a high molecular weight fraction and a low molecular weight fraction.
It would be desirable to provide a diafiltration system wherein the means for adding diluent to the high molecular weight fraction in the recirculation loop promotes efficient separation without the need for excessive separation membrane area or excessive dilution. Furthermore, it would be highly desirable to provide a method for effecting plasmapheresis which includes a step of fractionating the plasma fraction into a high molecular weight fraction and a low molecular weight fraction whereby the plasma membrane filtration surface area can be minimized. Also, it would be desirable to provide such a process and apparatus whereby the flux across the plasma separation membrane as well as the albumin permeation through the membrane could be accurately predicted and controlled so that the high molecular weight protein removal can be accurately estimated and the albumin make up, if any, can be accurately estimated.